Up-regulation of CXC chemokines and their receptors: implications for proinflammatory microenvironments of ovarian carcinomas and endometriosis

• Published in: Human pathology 2007-11, Vol.38 (11), p.1676-1687
• Main Authors: Furuya, Mitsuko, MD, PhD, Suyama, Takahito, MD, PhD, Usui, Hirokazu, MD, PhD, Kasuya, Yoshitoshi, PhD, Nishiyama, Mariko, MD, PhD, Tanaka, Naotake, MD, PhD, Ishiwata, Isamu, MD, PhD, Nagai, Yuichiro, MD, PhD, Shozu, Makio, MD, PhD, Kimura, Sadao, PhD
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological and medical sciences; Cell Line, Tumor; Chemokine; Chemokine CXCL1 - biosynthesis; Chemokine CXCL11 - biosynthesis; Chemokine CXCL12 - biosynthesis; Chemokine CXCL5 - biosynthesis; Chemokine CXCL9 - biosynthesis; Chemokines, CXC - biosynthesis; Endometriosis; Endometriosis - physiopathology; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; IFN- γ; Immunohistochemistry; Interleukin-8 - biosynthesis; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Middle Aged; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - physiopathology; Ovary - metabolism; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Proteins; Receptors, CXCR - biosynthesis; Receptors, CXCR3 - biosynthesis; Receptors, CXCR4 - biosynthesis; Rodents; Tumors; Up-Regulation
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2007.03.023

Summary Molecular abnormalities in the epithelial cells of endometriosis and their relevance to carcinogenesis of the ovary have been well studied. On the other hand, the differences of proinflammatory microenvironments between endometriosis and ovarian carcinomas have not been well documented yet. In this study, the expression patterns of CXC chemokines (IL-8, ENA-78, GRO- α , I-TAC, Mig, and SDF-1) and their receptors (CXCR2, CXCR3, and CXCR4) were compared among 12 ovarian carcinomas, 8 endometriosis, and 6 normal ovaries using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. The CXCR3-mediated signaling in ovarian carcinoma cells in vitro was also investigated. In quantitative reverse transcriptase polymerase chain reaction, ENA-78 was up-regulated both in endometriosis and carcinomas, whereas I-TAC was detected exclusively in carcinomas. CXCR3 was up-regulated both in carcinomas and endometriosis. However, immunohistochemical studies revealed that the localization of CXCR3 in carcinomas was distinctively different from that in endometriosis. In carcinoma-endometriosis coexisting cases, CXCR3-positive lymphocytes in benign lesions decreased in proportion as CXCR3-positive tumor cells replaced the tissues. CXCR3 was also detected in ovarian carcinoma cell lines in vitro. Administration of interferon γ (IFN- γ )–inducible chemokines induced extracellular signal-regulated kinase phosphorylation in these carcinoma cells. The results indicated that CXC chemokines might contribute to the progression of ovarian carcinomas and endometriosis in different manners. Aberrant expression of IFN- γ –inducible chemokines and CXCR3 in carcinoma cells in association with reduced CXCR3-positive immune cells raised the possibility that IFN- γ –inducible chemokines might not exert effective antitumor immune responses but that they might work in favor of tumor progression.